Dataset Information

Alternatively spliced down syndrome cell adhesion molecule (Dscam) controls innate immunity in crab.

ABSTRACT: Alternatively-spliced hypervariable immunoglobulin domain-encoding molecules, called Down syndrome cell adhesion molecule (Dscam), have been widely detected as components of the arthropod immune system. Although its ability to specifically bind pathogens and enable phagocytosis of bacteria has been elucidated, the signal transduction mechanisms or effectors that activate post-Dscam-binding pathogens remain poorly characterized. Here, we reveal the alternative splicing exons of Dscam's cytoplasmic tail and its isoforms in the hemocytes of crab (Eriocheir sinensis), showing that the expression of Dscam was acutely induced after an immune challenge, which suggested its functioning for innate immunity. Significantly decreased expression levels of antimicrobial molecular peptides (AMPs) were detected in Dscam-silenced crab hemocytes in vitro, which coincided with their vulnerability to infection by Staphylococcus aureus and higher bacterial concentrations occurring in Dscam-silenced crabs in vivo Further experimental investigation demonstrated that Dscam-regulated AMP expression via the Src homology (SH)3-binding domain in the first constant exon translated protein of the cytoplasmic tail bound with the SH3 domain of the Dock, an SH3/SH2 adaptor protein required for axon guidance. Dock promoted extracellular signal-regulated kinase (ERK) phosphorylation via indirect binding and then regulated dorsal phosphorylation and translocation from the cytoplasm to the nucleus, subsequently promoting AMP expression for the effective removal of bacteria. To the best of our knowledge, this comprehensive study is the first to highlight the critical role of the alternatively-spliced Dscam cytoplasmic tail in antimicrobial control activity. It also suggests possible cross-talk occurring between Dscam and other pattern recognition receptors.

SUBMITTER: Li D

PROVIDER: S-EPMC6827295 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Alternatively spliced down syndrome cell adhesion molecule (Dscam) controls innate immunity in crab.

Li Dan D Wan Zhicheng Z Li Xuejie X Duan Ming M Yang Lei L Ruan Zechao Z Wang Qun Q Li Weiwei W

The Journal of biological chemistry 20190919 44

Alternatively-spliced hypervariable immunoglobulin domain-encoding molecules, called Down syndrome cell adhesion molecule (Dscam), have been widely detected as components of the arthropod immune system. Although its ability to specifically bind pathogens and enable phagocytosis of bacteria has been elucidated, the signal transduction mechanisms or effectors that activate post-Dscam-binding pathogens remain poorly characterized. Here, we reveal the alternative splicing exons of Dscam's cytoplasmi ...[more]

PMID: 31537644

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Project description:The Dscam gene in the fruit fly, Drosophila melanogaster, contains twenty-four exons, four of which are composed of tandem arrays that each undergo mutually exclusive alternative splicing (4, 6, 9 and 17), potentially generating 38,016 protein isoforms. This degree of transcript diversity has not been found in mammalian homologs of Dscam. We examined the molecular evolution of exons within this gene family to locate the point of divergence for this alternative splicing pattern.Using the fruit fly Dscam exons 4, 6, 9 and 17 as seed sequences, we iteratively searched sixteen genomes for homologs, and then performed phylogenetic analyses of the resulting sequences to examine their evolutionary history. We found homologs in the nematode, arthropod and vertebrate genomes, including homologs in several vertebrates where Dscam had not been previously annotated. Among these, only the arthropods contain homologs arranged in tandem arrays indicative of mutually exclusive splicing. We found no homologs to these exons within the Arabidopsis, yeast, tunicate or sea urchin genomes but homologs to several constitutive exons from fly Dscam were present within tunicate and sea urchin. Comparing the rate of turnover within the tandem arrays of the insect taxa (fruit fly, mosquito and honeybee), we found the variants within exons 4 and 17 are well conserved in number and spatial arrangement despite 248-283 million years of divergence. In contrast, the variants within exons 6 and 9 have undergone considerable turnover since these taxa diverged, as indicated by deeply branching taxon-specific lineages.Our results suggest that at least one Dscam exon array may be an ancient duplication that predates the divergence of deuterostomes from protostomes but that there is no evidence for the presence of arrays in the common ancestor of vertebrates. The different patterns of conservation and turnover among the Dscam exon arrays provide a striking example of how a gene can evolve in a modular fashion rather than as a single unit.

Project description:BACKGROUND:Synonymous codon usage is typically biased towards translationally superior codons in many organisms. In Drosophila, genomic data indicates that translationally optimal codons and splice optimal codons are mostly mutually exclusive, and adaptation to translational efficiency is reduced in the intron-exon boundary regions where potential exonic splicing enhancers (ESEs) reside. In contrast to genomic scale analyses on large datasets, a refined study on a well-controlled set of samples can be effective in demonstrating the effects of particular splice-related factors. Down syndrome cell adhesion molecule (Dscam) has the largest number of alternatively spliced exons (ASEs) known to date, and the splicing frequency of each ASE is accessible from the relative abundance of the transcript. Thus, these ASEs comprise a unique model system for studying the effect of splicing regulation on synonymous codon usage. RESULTS:Codon Bias Indices (CBI) in the 3' boundary regions were reduced compared to the rest of the exonic regions among 48 and 33 ASEs of exon 6 and 9 clusters, respectively. These regional differences in CBI were affected by splicing frequency and distance from adjacent exons. Synonymous divergence levels between the 3' boundary region and the remaining exonic region of exon 6 ASEs were similar. Additionally, another sensitive comparison of paralogous exonic regions in recently retrotransposed processed genes and their parental genes revealed that, in the former, the differences in CBI between what were formerly the central regions and the boundary regions gradually became smaller over time. CONCLUSION:Analyses of the multiple ASEs of Dscam allowed direct tests of the effect of splice-related factors on synonymous codon usage and provided clear evidence that synonymous codon usage bias is restricted by exonic splicing signals near the intron-exon boundary. A similar synonymous divergence level between the different exonic regions suggests that the intensity of splice-related selection is generally weak and comparable to that of translational selection. Finally, the leveling off of differences in codon bias over time in retrotransposed genes meets the direct prediction of the tradeoff model that invokes conflict between translational superiority and splicing regulation, and strengthens the conclusions obtained from Dscam.

Dataset Information

Alternatively spliced down syndrome cell adhesion molecule (Dscam) controls innate immunity in crab.

Publications

Alternatively spliced down syndrome cell adhesion molecule (Dscam) controls innate immunity in crab.

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